1. Field of Invention
The present invention relates to design and synthesis of novel benzoylphenylurea (BPU) sulfur analogs with increased potency and enhanced water solubility. More specifically, the present invention is directed toward the synthesis of sulfur, hydroximic acid, and boronic acid analogs of BPU.
2. Brief Description of Art
The lack of selectivity of many cancer agents and the occurrence of intrinsic or acquired resistance of tumors to chemotherapy have been major obstacles in the treatment of cancer. Microtubules, which are key components of the cell, play an important role in a variety of cellular process, including mitosis and cell division. See, Downing, K. H., et al., Curr. Opin. Struct. Biol., 8:785-791 (1998) and Sorger, P. K., et al., Curr. Opin. Cell Biol., 9:807-814 (1997). Antimitotic agents can be divided into two major classes: (1) microtubule stabilizers such as paclitaxel and docetaxel, which prevent the depolymerization of tubulin (Jordan, A., et al., Med. Res. Rev., 18:259-296 (1998)); and (2) Vinca alkaloids (e.g., vincristine, vinblastine, and vinorelbine) and colchicines, which inhibit the polymerization of tubulin (Jordan, A., et al., Med. Res. Rev., 18:259-296 (1998)). Although some of these agents have been used as antiproliferative agents in the treatment of human malignancies, they suffer from drug resistance mediated through the expression of efflux pumps. See, Lehnert, M., Eur. J. Cancer, 32A:912-920 (1996) and Germann, U. A., Eur. J. Cancer, 32A:927-944 (1996).
Urea and thiourea derivatives have been used for the treatment of a wide range of solid tumors, Easmon, J. et al.; J. Med. Chem., 44:2164-2171 (2001). Urea-based prodrugs have been reported as candidates for melanocyte-directed enzyme prodrug therapy (MDEPT), in which they release the drug upon exposure to tyrosinase. See, Jordan, A. M. et al., Bioorg. Med. Chem., 10:2625-2633 (2002). Benzoylphenylurea (BPU) compounds were originally developed as insecticides, and their antitumor activity was found during random screening (Okada, H., et al., Chem. Pharm. Bull., 39:2308-2315 (1991)). Various analogues of BPU were synthesized, and their cytotoxic activity was examined to establish structure-activity relationships (Okada, H., et al, Chem. Pharm. Bull., 39:2308-2315 (1991)). To improve physicochemical properties, organic and water soluble BPU derivatives were developed. See, Okada, H., et al., Chem. Pharm. Bull., 42:57-61 (1994); and Okada, H., et al., Chem. Pharm. Bull., 47:430-433 (1999). Six of these analogues were screened at the NCI for their cytotoxicity against various cancer cell lines. They exhibited potent antitumor activity in vitro against several cancer cell lines, as well in vivo against several tumor models. These compounds also have been reported to be effective inhibitors of tubulin polymerization (Holligshead, M. G., et al., Proc. Am. Assoc. Cancer Res., 39:164 (1979)). One of these agents, compound 1 (NSC-639829),
(Holligshead, M. G., et al, Proc. Am. Assoc. Cancer Res., 39:164 (1979)) is currently being evaluated in Phase I clinical trials in patients with refractory metastatic cancer. See, Messersmith, W. A., et al., Proc. Am. Soc. Clin. Oncol., 22:203 (2003); and Edelman, M. J., et al., Proc. Am. Soc. Clin. Oncol., 22:137 (2003). We have previously reported the synthesis and antitumor evaluation of a set of BPU analogues (Gurulingappa, H., et al., Bioorg. Med. Chem. Lett., 14:2213-2216 (2004)).
There is still a need to improve physicochemical properties, organic and water soluble BPU derivatives. To that end the present invention discloses a novel series of synthesized derivatives of BPU by replacing the urea moiety with thiourea and the ether linkage with sulfide, sulfoxide, or sulfone groups. The activity of such novel agents, are significantly more toxic to cancer cells in culture.